Publications by authors named "Samuel M Meier-Menches"

28 Publications

  • Page 1 of 1

Metabo-tip: a metabolomics platform for lifestyle monitoring supporting the development of novel strategies in predictive, preventive and personalised medicine.

EPMA J 2021 Jun 4;12(2):141-153. Epub 2021 May 4.

Department of Analytical Chemistry, Faculty of Chemistry, University Vienna, Vienna, Austria.

Background/aims: Exposure to bioactive compounds from nutrition, pharmaceuticals, environmental contaminants or other lifestyle habits may affect the human organism. To gain insight into the effects of these influences, as well as the fundamental biochemical mechanisms behind them, individual molecular profiling seems to be a promising tool and may support the further development of predictive, preventive and personalised medicine.

Methods: We developed an assay, called metabo-tip for the analysis of sweat, collected from fingertips, using mass spectrometry-by far the most comprehensive and sensitive method for such analyses. To evaluate this assay, we exposed volunteers to various xenobiotics using standardised protocols and investigated their metabolic response.

Results: As early as 15 min after the consumption of a cup of coffee, 50 g of dark chocolate or a serving of citrus fruits, significant changes in the sweat composition of the fingertips were observed, providing relevant information in regard to the ingested substances. This included not only health-promoting bioactive compounds but also potential hazardous substances. Furthermore, the identification of metabolites from orally ingested medications such as metamizole indicated the applicability of this assay to observe specific enzymatic processes in a personalised fashion. Remarkably, we found that the sweat composition fluctuated in a diurnal rhythm, supporting the hypothesis that the composition of sweat can be influenced by endogenous metabolic activities. This was further corroborated by the finding that histamine was significantly increased in the metabo-tip assay in individuals with allergic reactions.

Conclusion: Metabo-tip analysis may have a large number of practical applications due to its analytical power, non-invasive character and the potential of frequent sampling, especially regarding the individualised monitoring of specific lifestyle and influencing factors. The extraordinarily rich individualised metabolomics data provided by metabo-tip offer direct access to individual metabolic activities and will thus support predictive preventive personalised medicine.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-021-00241-6.
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http://dx.doi.org/10.1007/s13167-021-00241-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192631PMC
June 2021

Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs.

Angew Chem Int Ed Engl 2021 06 6;60(24):13405-13413. Epub 2021 May 6.

Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel Au cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated Au fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.
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http://dx.doi.org/10.1002/anie.202102266DOI Listing
June 2021

Daily Caffeine Intake Induces Concentration-Dependent Medial Temporal Plasticity in Humans: A Multimodal Double-Blind Randomized Controlled Trial.

Cereb Cortex 2021 May;31(6):3096-3106

Centre for Chronobiology, University Psychiatric Clinics, University of Basel, 4002 Basel, Switzerland.

Caffeine is commonly used to combat high sleep pressure on a daily basis. However, interference with sleep-wake regulation could disturb neural homeostasis and insufficient sleep could lead to alterations in human gray matter. Hence, in this double-blind, randomized, cross-over study, we examined the impact of 10-day caffeine (3 × 150 mg/day) on human gray matter volumes (GMVs) and cerebral blood flow (CBF) by fMRI MP-RAGE and arterial spin-labeling sequences in 20 habitual caffeine consumers, compared with 10-day placebo (3 × 150 mg/day). Sleep pressure was quantified by electroencephalographic slow-wave activity (SWA) in the previous nighttime sleep. Nonparametric voxel-based analyses revealed a significant reduction in GMV in the medial temporal lobe (mTL) after 10 days of caffeine intake compared with 10 days of placebo, voxel-wisely adjusted for CBF considering the decreased perfusion after caffeine intake compared with placebo. Larger GMV reductions were associated with higher individual concentrations of caffeine and paraxanthine. Sleep SWA was, however, neither different between conditions nor associated with caffeine-induced GMV reductions. Therefore, the data do not suggest a link between sleep depth during daily caffeine intake and changes in brain morphology. In conclusion, daily caffeine intake might induce neural plasticity in the mTL depending on individual metabolic processes.
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http://dx.doi.org/10.1093/cercor/bhab005DOI Listing
May 2021

Spectroelectrochemical Properties and Catalytic Activity in Cyclohexane Oxidation of the Hybrid Zr/Hf-Phthalocyaninate-Capped Nickel(II) and Iron(II) tris-Pyridineoximates and Their Precursors.

Molecules 2021 Jan 11;26(2). Epub 2021 Jan 11.

Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria.

The in situ spectroelectrochemical cyclic voltammetric studies of the antimony-monocapped nickel(II) and iron(II) tris-pyridineoximates with a labile triethylantimony cross-linking group and Zr(IV)/Hf(IV) phthalocyaninate complexes were performed in order to understand the nature of the redox events in the molecules of heterodinuclear zirconium(IV) and hafnium(IV) phthalocyaninate-capped derivatives. Electronic structures of their 1e-oxidized and 1e-electron-reduced forms were experimentally studied by electron paramagnetic resonance (EPR) spectroscopy and UV-vis-near-IR spectroelectrochemical experiments and supported by density functional theory (DFT) calculations. The investigated hybrid molecular systems that combine a transition metal (pseudo)clathrochelate and a Zr/Hf-phthalocyaninate moiety exhibit quite rich redox activity both in the cathodic and in the anodic region. These binuclear compounds and their precursors were tested as potential catalysts in oxidation reactions of cyclohexane and the results are discussed.
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http://dx.doi.org/10.3390/molecules26020336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827310PMC
January 2021

Interaction with Ribosomal Proteins Accompanies Stress Induction of the Anticancer Metallodrug BOLD-100/KP1339 in the Endoplasmic Reticulum.

Angew Chem Int Ed Engl 2021 03 1;60(10):5063-5068. Epub 2021 Feb 1.

Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 38, 1090, Vienna, Austria.

The ruthenium-based anticancer agent BOLD-100/KP1339 has shown promising results in several in vitro and in vivo tumour models as well as in early clinical trials. However, its mode of action remains to be fully elucidated. Recent evidence identified stress induction in the endoplasmic reticulum (ER) and concomitant down-modulation of HSPA5 (GRP78) as key drug effects. By exploiting the naturally formed adduct between BOLD-100 and human serum albumin as an immobilization strategy, we were able to perform target-profiling experiments that revealed the ribosomal proteins RPL10, RPL24, and the transcription factor GTF2I as potential interactors of this ruthenium(III) anticancer agent. Integrating these findings with proteomic profiling and transcriptomic experiments supported ribosomal disturbance and concomitant induction of ER stress. The formation of polyribosomes and ER swelling of treated cancer cells revealed by TEM validated this finding. Thus, the direct interaction of BOLD-100 with ribosomal proteins seems to accompany ER stress-induction and modulation of GRP78 in cancer cells.
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http://dx.doi.org/10.1002/anie.202015962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986094PMC
March 2021

Plecstatin-1 induces an immunogenic cell death signature in colorectal tumour spheroids.

Metallomics 2020 12;12(12):2121-2133

Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090, Vienna, Austria.

Organometallic metal(arene) anticancer agents were believed to confer low selectivity for potential cellular targets. However, the ruthenium(arene) pyridinecarbothioamide (plecstatin-1) showed target selectivity for plectin, a scaffold protein and cytolinker. We employed a three-dimensional cancer spheroid model and showed that plecstatin-1 limited spheroid growth, induced changes in the morphology and in the architecture of tumour spheroids by disrupting the cytoskeletal organization. Additionally, we demonstrated that plecstatin-1 induced oxidative stress, followed by the induction of an immunogenic cell death signature through phosphorylation of eIF2α, exposure of calreticulin, HSP90 and HSP70 on the cell membrane and secretion of ATP followed by release of high mobility group box-1.
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http://dx.doi.org/10.1039/d0mt00227eDOI Listing
December 2020

Sensing of Proteins by ICD Response of Iron(II) Clathrochelates Functionalized by Carboxyalkylsulfide Groups.

Biomolecules 2020 11 26;10(12). Epub 2020 Nov 26.

Institute of Molecular Biology and Genetics NASU, 150 Zabolotnogo St., 03143 Kyiv, Ukraine.

Recognition of elements of protein tertiary structure is crucial for biotechnological and biomedical tasks; this makes the development of optical sensors for certain protein surface elements important. Herein, we demonstrated the ability of iron(II) clathrochelates (-) functionalized with mono-, di- and hexa-carboxyalkylsulfide to induce selective circular dichroism (CD) response upon binding to globular proteins. Thus, inherently CD-silent clathrochelates revealed selective inducing of CD spectra when binding to human serum albumin (HSA) (, ), beta-lactoglobuline () and bovine serum albumin (BSA) (). Hence, functionalization of iron(II) clathrochelates with the carboxyalkylsulfide group appears to be a promising tool for the design of CD-probes sensitive to certain surface elements of proteins tertiary structure. Additionally, interaction of - with proteins was also studied by isothermal titration calorimetry, protein fluorescence quenching, electrospray ionization mass spectrometry (ESI-MS) and computer simulations. Formation of both 1:1 and 1:2 assemblies of HSA with - was evidenced by ESI-MS. A protein fluorescence quenching study suggests that binds with both BSA and HSA via the sites close to Trp residues. Molecular docking calculations indicate that for both BSA and HSA, binding of to Site I and to an "additional site" is more favorable energetically than binding to Site II.
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http://dx.doi.org/10.3390/biom10121602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759900PMC
November 2020

An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells.

Chemistry 2020 Dec 3;26(67):15528-15537. Epub 2020 Nov 3.

Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 38, 1090, Vienna, Austria.

The organometallic Au bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene) ] (AuTMX ) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX in the cellular context using mass spectrometry-based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal-based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.
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http://dx.doi.org/10.1002/chem.202003495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756355PMC
December 2020

Exploring the Chemoselectivity towards Cysteine Arylation by Cyclometallated Au Compounds: New Mechanistic Insights.

Chembiochem 2020 11 8;21(21):3071-3076. Epub 2020 Jul 8.

Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85747, Garching, Germany.

To gain more insight into the factors controlling efficient cysteine arylation by cyclometallated Au complexes, the reaction between selected gold compounds and different peptides was investigated by high-resolution liquid chromatography electrospray ionization mass spectrometry (HR-LC-ESI-MS). The deduced mechanisms of C-S cross-coupling, also supported by density functional theory (DFT) and quantum mechanics/molecular mechanics (QM/MM) calculations, evidenced the key role of secondary peptidic gold binding sites in favouring the process of reductive elimination.
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http://dx.doi.org/10.1002/cbic.202000262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689846PMC
November 2020

Investigations on the Anticancer Potential of Benzothiazole-Based Metallacycles.

Front Chem 2020 3;8:209. Epub 2020 Apr 3.

Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.

A series of 2-phenylbenzothiazole derivatives and their corresponding organometallic ruthenium(II) and osmium(II) complexes were synthesized, designed to exploit both, the attributes of the half-sandwich transition metal scaffold and the bioactivity spectrum of the applied 2-phenylbenzothiazoles. All synthesized compounds were characterized via standard analytical methods. The obtained organometallics showed antiproliferative activity in the low μM range and are thus at least an order of magnitude more potent than the free ligands. ESI-MS measurements showed that the examined compounds were stable in aqueous solution over 48 h. Additionally, their binding preferences to small biomolecules, their cellular accumulation and capacity of inducing apoptosis/necrosis were investigated. Based on the fluorescence properties of the selected ligand and the corresponding ruthenium complex, their subcellular distribution was studied by fluorescence microscopy, revealing a high degree of colocalization with acidic organelles of cancer cells.
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http://dx.doi.org/10.3389/fchem.2020.00209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147246PMC
April 2020

Design Strategies and Medicinal Applications of Metal-Peptidic Bioconjugates.

Bioconjug Chem 2020 05 14;31(5):1279-1288. Epub 2020 Apr 14.

Chair of Medicinal and Bioinorganic Chemistry, Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85748 Garching, Germany.

The conjugation of metal-based scaffolds to peptides, proteins, or antibodies allows the systemic targeting of these payloads to specific locations in the body, such as target cells/tissues (e.g., cancer) and subcellular compartments, for either therapy or imaging. This Topical Review includes an overview of the available chemical strategies to achieve metal-peptidic bioconjugates for biomedical applications, focusing on the types of chemical functionalities used to tether the drug to the peptide directly or indirectly. Central to all the possible approaches is the development of highly efficient and selective bioconjugation reactions that operate under mild, peptide-compatible conditions. For each strategy, selected examples are highlighted with particular emphasis to the studies reporting the therapeutic effects of the metal-peptidic conjugates in the treatment of cancer. Overall, some of the herewith discussed cases clearly hold promise for translation into clinically meaningful applications in the field of targeted therapeutics. Nevertheless, novel chemical approaches enabling the chemoselective metalation of specific residues in peptides under biologically friendly conditions, as well as the design of stimuli-responsive bioconjugates, are still expected to emerge. Certainly, the peculiar biorthogonal reactivity of metallodrugs provides an enlarged toolbox of opportunities for bioconjugation. Therefore, we outline a number of possible future directions and applications.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00152DOI Listing
May 2020

Lipid droplet-mediated scavenging as novel intrinsic and adaptive resistance factor against the multikinase inhibitor ponatinib.

Int J Cancer 2020 09 2;147(6):1680-1693. Epub 2020 Mar 2.

Department of Medicine I, Medical University of Vienna, Institute of Cancer Research and Comprehensive Cancer Center, Vienna, Austria.

Ponatinib is a small molecule multi-tyrosine kinase inhibitor clinically approved for anticancer therapy. Molecular mechanisms by which cancer cells develop resistance against ponatinib are currently poorly understood. Likewise, intracellular drug dynamics, as well as potential microenvironmental factors affecting the activity of this compound are unknown. Cell/molecular biological and analytical chemistry methods were applied to investigate uptake kinetics/subcellular distribution, the role of lipid droplets (LDs) and lipoid microenvironment compartments in responsiveness of FGFR1-driven lung cancer cells toward ponatinib. Selection of lung cancer cells for acquired ponatinib resistance resulted in elevated intracellular lipid levels. Uncovering intrinsic ponatinib fluorescence enabled dissection of drug uptake/retention kinetics in vitro as well as in mouse tissue cryosections, and revealed selective drug accumulation in LDs of cancer cells. Pharmacological LD upmodulation or downmodulation indicated that the extent of LD formation and consequent ponatinib incorporation negatively correlated with anticancer drug efficacy. Co-culturing with adipocytes decreased ponatinib levels and fostered survival of cancer cells. Ponatinib-selected cancer cells exhibited increased LD levels and enhanced ponatinib deposition into this organelle. Our findings demonstrate intracellular deposition of the clinically approved anticancer compound ponatinib into LDs. Furthermore, increased LD biogenesis was identified as adaptive cancer cell-defense mechanism via direct drug scavenging. Together, this suggests that LDs represent an underestimated organelle influencing intracellular pharmacokinetics and activity of anticancer tyrosine kinase inhibitors. Targeting LD integrity might constitute a strategy to enhance the activity not only of ponatinib, but also other clinically approved, lipophilic anticancer therapeutics.
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http://dx.doi.org/10.1002/ijc.32924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497038PMC
September 2020

Comparative biological evaluation and G-quadruplex interaction studies of two new families of organometallic gold(I) complexes featuring N-heterocyclic carbene and alkynyl ligands.

J Inorg Biochem 2020 01 11;202:110844. Epub 2019 Sep 11.

School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF103AT, United Kingdom. Electronic address:

Experimental organometallic gold(I) compounds hold promise for anticancer therapy. This study reports the synthesis of two novel families of gold(I) complexes, including N1-substituted bis-N-heterocyclic carbene (NHC) complexes of general formula [Au(N1-TBM)]BF (N1-TBM = N1-substituted 9-methyltheobromin-8-ylidene) and mixed gold(I) NHC-alkynyl complexes, [Au(N1-TBM)alkynyl]. The compounds were fully characterised for their structure and stability in aqueous environment and in the presence of N-acetyl cysteine by nuclear magnetic resonance (NMR) spectroscopy. The structures of bis(1-ethyl-3,7,9-trimethylxanthin-8-ylidene)gold(I), (4-ethynylpyridine)(1,9-dimethyltheobromine-8-ylidene)gold(I) and of (2,8-Diethyl-10-(4-ethynylphenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ,5λ-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine)(1,3,7,9-tetramethylxanthin-8-ylidene)gold(I) were also confirmed by X-ray diffraction analysis. The compounds were studied for their properties as DNA G-quadruplex (G4 s) stabilizers by fluorescence resonance energy transfer (FRET) DNA melting. Only the cationic [Au(N1-TBM)]BF family showed moderate G4 stabilization properties with respect to the previously reported benchmark compound [Au(9-methylcaffein-8-ylidene)] (AuTMX). However, the compounds also showed marked selectivity for binding to G4 structures with respect to duplex DNA in competition experiments. For selected complexes, the interactions with G4 s were also confirmed by circular dichroism (CD) studies. Furthermore, the gold(I) complexes were assessed for their antiproliferative effects in human cancer cells in vitro, displaying moderate activity. Of note, among the mixed gold(I) NHC-alkynyl compounds, one features a fluorescent boron-dipyrromethene (BODIPY) moiety which allowed determining its uptake into the cytoplasm of cancer cells by fluorescence microscopy.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110844DOI Listing
January 2020

The antifibrotic potential of a sustained release formulation of a PDGFβ-receptor targeted rho kinase inhibitor.

J Control Release 2019 02 22;296:250-257. Epub 2019 Jan 22.

Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands. Electronic address:

Rho kinase activity in hepatic stellate cells (HSCs) is associated with activation, transformation and contraction of these cells, leading to extracellular matrix production and portal hypertension in liver cirrhosis. Inhibition of rho kinase activity can reduce these activities, but may also lead to side effects, for instance systemic hypotension. This can be circumvented by liver-specific delivery of a rho kinase inhibitor to effector cells. Therefore, we targeted the rho kinase inhibitor Y27632 to the key pathogenic cells in liver fibrosis, i.e. myofibroblasts including activated HSCs that highly express the PDGFβ-receptor, using the drug carrier pPB-MSA. This carrier consists of mouse serum albumin (MSA) covalently coupled to several PDGFβR-recognizing moieties (pPB). We aimed to create a prolonged release system of such a targeted construct, by encapsulating pPB-MSA-Y27632 in biodegradable polymeric microspheres, thereby reducing short-lasting peak concentrations and the need for frequent administrations. Firstly, we confirmed the vasodilating potency of PDGFβ-receptor targeted Y27632 in vitro in a contraction assay using HSCs seeded on a collagen gel. We subsequently demonstrated the in vivo antifibrotic efficacy of pPB-MSA-Y27632-loaded microspheres in the Mdr2-/- mouse model of progressive biliary liver fibrosis. A single subcutaneous microsphere administration followed by organ harvest one week later clearly attenuated liver fibrosis progression and significantly suppressed the expression of fibrosis related genes, such as several collagens, profibrotic cytokines and matrix metalloproteinases. In conclusion, we demonstrate that polymeric microspheres are suitable as drug delivery system for the sustained systemic delivery of targeted protein constructs with antifibrotic potential, such as pPB-MSA-Y27632. This formulation appears suitable for the sustained treatment of liver fibrosis and possibly other chronic diseases.
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http://dx.doi.org/10.1016/j.jconrel.2018.12.039DOI Listing
February 2019

New Variations on the Theme of Gold(III) CNN Cyclometalated Complexes as Anticancer Agents: Synthesis and Biological Characterization.

Inorg Chem 2018 Dec 20;57(23):14852-14865. Epub 2018 Nov 20.

Dipartimento di Chimica e Farmacia , Università degli Studi di Sassari , via Vienna 2 , 07100 Sassari , Italy.

A series of novel (CNN) cyclometalated Au complexes of general formula [Au(bipy-H)X][PF] (bipy-H = CNN cyclometalated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine) were prepared with a range of anionic ligands X in the fourth coordination position, featuring C (alkynyl)-, N-, O-, or S-donor atoms. The X ligands are varied in nature and include three coumarins, 4-ethynylaniline, saccharine, and thio-β-d-glucose tetraacetate, the tripeptide glutathione (GSH), and a coumarin-substituted amide derived from 4-ethynylaniline. The gold(I) complex [Au(CArNHCOQ)(PPh)] (HCArNHCOQ = N-(4-ethynylphenyl)-2-oxo-2 H-chromene-3-carboxamide) was also prepared for comparison. The new compounds were fully characterized by means of analytical techniques, including NMR, absorption, and emission spectroscopy. The crystal structures of three cyclometalated Au complexes and of the Au derivative were solved by single-crystal X-ray diffraction. The antiproliferative activity of the new Au cyclometalated derivatives was evaluated against cancer cells in vitro. According to the obtained results, only complexes 3-PF and 5-PF, featuring coumarins as ancillary ligands and endowed with high redox stability in solution, display antiproliferative effects, with 5-PF being the most potent, while all of the others are scarcely active to nonactive in the selected cell lines. In order to study the reactivity of the compounds with biomolecules, the interaction of complexes 3-PF and 5-PF with the protein cytochrome c and the amino acids cysteine and histidine was analyzed by electrospray ionization mass spectrometry (ESI MS), showing adduct formation only with Cys after at least 1 h incubation. Furthermore, the parent hydroxo complex [Au(bipy-H)(OH)][PF] (1OH-PF) was investigated in a competitive assay to determine the protein vs oligonucleotide binding preferences by capillary zone electrophoresis (CZE) coupled to ESI-MS. Of note, the compound was found to selectively form adducts with the oligonucleotide over the protein upon ligand exchange with the hydroxido ligand. Adduct formation occurred within the first 10 min of incubation, demonstrating the preference of 1OH-PF for nucleotides in this setup. Overall, the obtained results point toward the possibility to selectively target DNA with gold(III) organometallics.
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http://dx.doi.org/10.1021/acs.inorgchem.8b02604DOI Listing
December 2018

Serum-binding properties of isosteric ruthenium and osmium anticancer agents elucidated by SEC-ICP-MS.

Monatsh Chem 2018 25;149(10):1719-1726. Epub 2018 Aug 25.

1Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.

Abstract: Size-exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) was used to study the serum-binding preferences of two metallodrugs with anticancer activities in vivo, namely the organoruthenium compound plecstatin-1 and its isosteric osmium analog. The complexes were administered intraperitoneally into mice bearing a CT-26 tumor. Comparing the total metal content of mouse whole blood and serum underlined that the metallodrugs are mainly located in serum and not in the cellular fraction of the blood samples. In mouse serum, both compounds were not only found to bind extensively to the serum albumin/transferrin fraction but also to immunoglobulins. Free drug was not observed in any of the samples indicating rapid protein binding of the metallodrugs. These findings were validated by spiking human serum with the respective compounds ex vivo. An NCI-60 screen is reported for the osmium analog, which revealed a relative selectivity for cancer cell lines of the ovary and the central nervous system with respect to plecstatin-1. Finally, a COMPARE 170 analysis revealed disruption of DNA synthesis as a possible treatment effect of the osmium-based drug candidate.

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http://dx.doi.org/10.1007/s00706-018-2280-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133104PMC
August 2018

Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cells.

Metallomics 2019 01;11(1):118-127

Department of Analytical Chemistry, University of Vienna, Vienna, Austria.

Activation kinetics of metallo-prodrugs control the types of possible interactions with biomolecules. The intact metallo-prodrug is able to engage with potential targets by purely non-covalent bonding, while the activated metallodrug can form additional coordination bonds. It is hypothesized that the additional coordinative bonding might be favourable with respect to the target selectivity of activated metallodrugs. Thus, a time-dependent shotgun proteomics study was conducted in HCT116 colon carcinoma cells with plecstatins, which are organoruthenium anticancer drug candidates. First, the target selectivity was evaluated in a time-dependent fashion, which accounted for their hydrolysis kinetics. The binding selectivity increased from 50- to 160-fold and the average specificity from 0.72 to 0.86, respectively, from the 2 h to the 4 h target profiling experiment. Target profiling after 19 h did not reveal significant enrichments, possibly due to deactivation of the probe via arene cleavage. Up to 450 interactors were identified in the target profiling experiments. A plecstatin analogue that substituted a hydrogen bond acceptor with a hydrogen bond donor abrogated the target selectivity for plectin in HCT116 whole cell lysates, underlining the necessity of this hydrogen bond acceptor for a strong interaction between plecstatin and plectin. Second, time-dependent response profiling experiments provided evidence that plecstatin-2 induced an integrated stress response (ISR) in HCT116 cell culture. The phosphorylation of eIF2α, a key mediator of the ISR, after 3 h treatment indicated that this perturbation was initiated by the intact plecstatin-2 prodrug, while the effects of plectin-targeting are mediated by activated plecstatin-2.
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http://dx.doi.org/10.1039/c8mt00152aDOI Listing
January 2019

Aquaporins in cancer development: opportunities for bioinorganic chemistry to contribute novel chemical probes and therapeutic agents.

Metallomics 2018 05;10(5):696-712

School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK.

Aquaporins (AQPs) are membrane proteins allowing permeation of water, glycerol & hydrogen peroxide across biomembranes, and playing an important role in water homeostasis in different organs, exocrine gland secretion, urine concentration, skin moisturization, fat metabolism and neural signal transduction. Notably, a large number of studies showed that AQPs are closely associated with cancer biological functions and expressed in more than 20 human cancer cell types. Furthermore, AQP expression is positively correlated with tumour types, grades, proliferation, migration, angiogenesis, as well as tumour-associated oedema, rendering these membrane channels attractive as both diagnostic and therapeutic targets in cancer. Recent developments in the field of AQPs modulation have identified coordination metal-based complexes as potent and selective inhibitors of aquaglyceroporins, opening new avenues in the application of inorganic compounds in medicine and chemical biology. The present review is aimed at providing an overview on AQP structure and function, mainly in relation to cancer. In this context, the exploration of coordination metal compounds as possible inhibitors of aquaporins may open the way to novel chemical approaches to study AQP roles in tumour growth and potentially to new drug families. Thus, we describe recent results in the field and reflect upon the potential of inorganic chemistry in providing compounds to modulate the activity of "elusive" membrane targets as the aquaporins.
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http://dx.doi.org/10.1039/c8mt00072gDOI Listing
May 2018

Bioimaging of isosteric osmium and ruthenium anticancer agents by LA-ICP-MS.

Metallomics 2018 03 7;10(3):388-396. Epub 2018 Mar 7.

Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria and Research Cluster 'Translational Cancer Therapy Research', University and Medical University of Vienna, Vienna, Austria.

Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to study the spatial distribution of two metallodrugs with anticancer activities in vivo, namely the organoruthenium plecstatin-1 (1) and its isosteric osmium analogue (2), in liver, kidneys, muscles and tumours of treated mice bearing a CT-26 tumour after single-dose i.p. administration. To the best of our knowledge, this is the first time that the spatial distribution of an osmium drug candidate has been investigated using LA-ICP-MS in tissues. Independent measurements of the average ruthenium and osmium concentration via microwave digestion and ICP-MS in organs and tumours were in good agreement with the LA-ICP-MS results. Matrix-matched standards (MMS) ranging from 1 to 30 μg g were prepared to quantify the spatial distributions of the metals and the average metal content of the MMS samples was additionally quantified by ICP-MS after microwave digestion. The recoveries for osmium and ruthenium in the MMS were 105% and 101% on average, respectively, validating the sample preparation procedure of the MMS. Preparation of MMS was carried out under an argon atmosphere to prevent oxidation of osmium-species to the volatile OsO. The highest metal concentrations were found in the liver, followed by kidney, lung and tumour tissues, while muscles displayed only very low quantities of the respective metal. Both metallodrugs accumulated in the cortex of the kidneys more strongly compared to the medulla. Interestingly, osmium from 2 was largely located at the periphery and tissue edges, whereas ruthenium from 1 was observed to penetrate deeper into the organs and tumours.
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http://dx.doi.org/10.1039/c8mt00012cDOI Listing
March 2018

Rollover Cyclometalated Bipyridine Platinum Complexes as Potent Anticancer Agents: Impact of the Ancillary Ligands on the Mode of Action.

Inorg Chem 2018 Mar 14;57(5):2851-2864. Epub 2018 Feb 14.

School of Chemical Sciences , University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand.

Platinum-based anticancer coordination compounds are widely used in the treatment of many tumor types, where they are very effective but also cause severe side effects. Organoplatinum compounds are significantly less investigated than the analogous coordination compounds. We report here rollover cyclometalated Pt compounds based on 2,2'-bipyridine which are demonstrated to be potent antitumor agents both in vitro and in vivo. Variation of the co-ligands on the Pt(2,2'-bipyridine) backbone resulted in the establishment of structure-activity relationships. They showed that the biological activity was in general inversely correlated with the reaction kinetics to biomolecules as shown for amino acids, proteins, and DNA. The less stable compounds caused higher reactivity with biomolecules and were shown to induce p53-dependent DNA damage. In contrast, the presence of bulky PTA and PPh ligands was demonstrated to cause lower reactivity and increased antineoplastic activity. Such compounds were devoid of DNA-damaging activity and induced ATF4, a component of the endoplasmic reticulum (ER) stress pathway. The lead complex inhibited tumor growth similar to oxaliplatin while showing no signs of toxicity in test mice. Therefore, we demonstrated that it is possible to fine-tune rollover-cyclometalated Pt(II) compounds to target different cancer pathways and be a means to overcome the side effects associated with cisplatin and analogous compounds in cancer chemotherapy.
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http://dx.doi.org/10.1021/acs.inorgchem.7b03210DOI Listing
March 2018

Selective targeting of PARP-1 zinc finger recognition domains with Au(iii) organometallics.

Chem Commun (Camb) 2018 Jan;54(6):611-614

School of Chemistry, Cardiff University, Main Building, Park Place, CF10 3AT Cardiff, UK.

The binding of Au(iii) complexes to the zinc finger domain of the anticancer drug target PARP-1 was studied using a hyphenated mass spectrometry approach combined with quantum mechanics/molecular mechanics (QM/MM) studies. Competition experiments were carried out, whereby each Au complex was exposed to two types of zinc fingers. Notably, the cyclometallated Au-C^N complex was identified as the most selective candidate to disrupt the PARP-1 zinc finger domain, forming distinct adducts compared to the coordination compound Auphen.
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http://dx.doi.org/10.1039/c7cc08406dDOI Listing
January 2018

Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia.

Mol Cell Proteomics 2018 02 1;17(2):290-303. Epub 2017 Dec 1.

From the ‡Department of Analytical Chemistry, Faculty of Chemistry,

B cell chronic lymphocytic leukemia (B-CLL), the most common type of leukemia in adults, is still essentially incurable despite the development of novel therapeutic strategies. This reflects the incomplete understanding of the pathophysiology of this disease. A comprehensive proteome analysis of primary human B-CLL cells and B cells from younger as well as elderly healthy donors was performed. For comparison, the chronic B cell leukemia cell line JVM-13 was also included. A principal component analysis comprising 6,945 proteins separated these four groups, placing B cells of aged-matched controls between those of young donors and B-CLL patients, while identifying JVM-13 as poorly related cells. Mass spectrometric proteomics data have been made fully accessible via ProteomeXchange with identifier PXD006570-PXD006572, PXD006576, PXD006578, and PXD006589-PXD006591. Remarkably, B cells from aged controls displayed significant regulation of proteins related to stress management in mitochondria and ROS stress such as DLAT, FIS1, and NDUFAB1, and DNA repair, including RAD9A, MGMT, and XPA. ROS levels were indeed found significantly increased in B cells but not in T cells or monocytes from aged individuals. These alterations may be relevant for tumorigenesis and were observed similarly in B-CLL cells. In B-CLL cells, some remarkable unique features like the loss of tumor suppressor molecules PNN and JARID2, the stress-related serotonin transporter SLC6A4, and high expression of ZNF207, CCDC88A, PIGR and ID3, otherwise associated with stem cell phenotype, were determined. Alterations of metabolic enzymes were another outstanding feature in comparison to normal B cells, indicating increased beta-oxidation of fatty acids and increased consumption of glutamine. Targeted metabolomics assays corroborated these results. The present findings identify a potential proteome signature for immune senescence in addition to previously unrecognized features of B-CLL cells and suggest that aging may be accompanied by cellular reprogramming functionally relevant for predisposing B cells to transform to B-CLL cells.
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http://dx.doi.org/10.1074/mcp.RA117.000425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795392PMC
February 2018

Structure-activity relationships for ruthenium and osmium anticancer agents - towards clinical development.

Chem Soc Rev 2018 Feb;47(3):909-928

University of Vienna, Department of Analytical Chemistry, Waehringer Str. 38, A-1090 Vienna, Austria.

Anticancer metallodrugs based on ruthenium and osmium are among the most investigated and advanced non-platinum metallodrugs. Inorganic drug discovery with these agents has undergone considerable advances over the past two decades and has currently two representatives in active clinical trials. As many ruthenium and osmium metallodrugs are prodrugs, a key question to be addressed is how the molecular reactivity of such metal-based therapeutics dictates the selectivity and the type of interaction with molecular targets. Within this frame, this review introduces the field by the examples of the most advanced ruthenium lead structures. Then, global structure-activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics. Determining and validating global mechanisms of action and molecular targets are still major current challenges. Moreover, significant efforts must be invested in screening in vivo tumor models that mimic human pathophysiology to increase the predictability for successful preclinical and clinical development of ruthenium and osmium metallodrugs.
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http://dx.doi.org/10.1039/c7cs00332cDOI Listing
February 2018

Characterization of Hydrophilic Gold(I) N-Heterocyclic Carbene (NHC) Complexes as Potent TrxR Inhibitors Using Biochemical and Mass Spectrometric Approaches.

Inorg Chem 2017 Nov 2;56(22):14237-14250. Epub 2017 Nov 2.

School of Chemistry, Cardiff University , Park Place, CF103AT Cardiff, U.K.

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 DNA-a higher-order DNA structure playing key roles in telomere function-was 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.
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http://dx.doi.org/10.1021/acs.inorgchem.7b02345DOI Listing
November 2017

Characterizing activation mechanisms and binding preferences of ruthenium metallo-prodrugs by a competitive binding assay.

J Inorg Biochem 2017 12 16;177:322-327. Epub 2017 Jul 16.

Research Cluster "Translational Cancer Therapy Research", University of Vienna, 1090 Vienna, Austria; Department of Analytical Chemistry, University of Vienna, Waehringer Str. 38, 1090 Vienna, Austria. Electronic address:

The activation mechanisms and reactivity of ruthenium metallo-prodrug lead structures were investigated in detail using capillary zone electrophoresis mass spectrometry (CZE-MS) in a time-dependent manner and by exposing to a protein/oligonucleotide mixture. The competitive assays were performed with sodium trans-[RuCl(HInd)] where Hind=indazole (NKP-1339), [(η-p-cymene)RuCl(pta)], where pta=1,3,5-triaza-7-phosphaadamantane (RAPTA-C) and [(η-biphenyl)RuCl(1,2-ethylenediamine)]PF (RM175). Molecular and quantitative information on binding preferences was obtained by coupling CZE to electrospray ionization MS (ESI-MS) and inductively coupled plasma MS (ICP-MS), respectively. A score system is presented that ranks the binding preferences of Ru complexes with nucleotides and demonstrated the following trend of decreasing selectivity after 24h: RM175 (0.89)>RAPTA-C (0.78)>NKP-1339 (0.40). As expected, the organometallic drug candidates RM175 and RAPTA-C underwent a halido/aqua ligand exchange reaction at the metal center and showed distinct reactivity towards the biomolecules. In particular, the protein/DNA binding sites of RAPTA-C in a mixture of protein (ubiquitin) and oligonucleotide (5'-dATTGGCAC-3') were located at single-amino acid and single-nucleotide resolution, respectively. Activated RAPTA-C bound selectively to Met1, adenine and cytosine in this setting, which contrasts with the selectivity of RM175 for guanine. Finally, activation products of NKP-1339 were detected corresponding to Ru(Hind) fragments coordinated to the oligonucleotide, which represents one of the few examples of a directly observed Ru adduct.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.07.010DOI Listing
December 2017

DNA or protein? Capillary zone electrophoresis-mass spectrometry rapidly elucidates metallodrug binding selectivity.

Chem Commun (Camb) 2017 Jul;53(57):8002-8005

Institute of Inorganic Chemistry, University of Vienna, Faculty of Chemistry, Waehringer Str. 42, 1090 Vienna, Austria.

A novel capillary zone electrophoresis-mass spectrometry (CZE-MS) approach allows the simultaneous characterization and quantification of the binding of metal-based anticancer agents to biomolecules. Moreover, for the first time, oligonucleotide metallation was resolved at single-nucleotide resolution by MS.
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http://dx.doi.org/10.1039/c7cc04582dDOI Listing
July 2017

On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging.

Chem Commun (Camb) 2017 Jul;53(59):8249-8260

Molecular Catalysis, Department of Chemistry, Catalysis Research Center, Technische Universität München, Lichtenbergstr. 4, 85747 Garching bei München, Germany.

Organometallic compounds currently occupy an important place in the field of medicinal inorganic chemistry due to the unique chemical properties of metal coordination compounds. Particularly, metal compounds ligated by N-heterocyclic carbenes (NHC) have shown high potential for biomedical applications as antimicrobial and anticancer agents during the recent 15 years. Although further studies are necessary to validate the modes of action of this family of compounds, a number of biological targets have been identified, including DNA secondary structures. This perspective review aims at providing an overview of the most representative examples of metal NHC complexes reacting with nucleic acids via different binding modes. It is organized according to the type of DNA secondary structure targeted by metal NHCs, highlighting the possible advantages of biomedical applications, including therapy and imaging.
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http://dx.doi.org/10.1039/c7cc03074fDOI Listing
July 2017

Post-digestion stabilization of osmium enables quantification by ICP-MS in cell culture and tissue.

Analyst 2017 Jun;142(13):2327-2332

Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria.

An orally active osmium anticancer compound was reliably quantified in the organs of treated mice by inductively coupled plasma-mass spectrometry (ICP-MS) by adding a stabilizing solution consisting of ascorbic acid, thiourea and EDTA during sample preparation and avoiding oxidizing conditions. The limits of detection (LOD) and quantification (LOQ) of Os were determined in liver tissue to be 0.02 and 0.075 μg kg, respectively. In spiked liver tissue, the internal precision showed a relative standard deviation (RSD) of 4%, a matrix recovery of 92% and a digestion recovery of 99%. A similar quantification protocol was developed for cellular accumulation studies in vitro. The cells were lysed with a non-oxidizing lysis buffer consisting of 150 mmol L NaCl, 1.0% Triton X-100, 0.1% SDS, and 50 mmol L Tris at pH 8.0 before adding the stabilizing solution. The osmium compound was compared with an isosteric ruthenium analogue and they displayed similar cellular accumulation and organ distribution profiles.
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http://dx.doi.org/10.1039/c7an00350aDOI Listing
June 2017