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Dive into the research topics where Matthias H. M. Klose is active.

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Featured researches published by Matthias H. M. Klose.


Angewandte Chemie | 2017

An Organoruthenium Anticancer Agent Shows Unexpected Target Selectivity For Plectin

Samuel M. Meier; Dominique Kreutz; Lilli Winter; Matthias H. M. Klose; Klaudia Cseh; Tamara Weiss; Andrea Bileck; Beatrix Alte; Johanna C. Mader; Samir Jana; Annesha Chatterjee; Arindam Bhattacharyya; Michaela Hejl; Michael A. Jakupec; Petra Heffeter; Walter Berger; Christian G. Hartinger; Bernhard K. Keppler; Gerhard Wiche; Christopher Gerner

Organometallic metal(arene) anticancer agents require ligand exchange for their anticancer activity and this is generally believed to confer low selectivity for potential cellular targets. However, using an integrated proteomics-based target-response profiling approach as a potent hypothesis-generating procedure, we found an unexpected target selectivity of a ruthenium(arene) pyridinecarbothioamide (plecstatin) for plectin, a scaffold protein and cytolinker, which was validated in a plectin knock-out model in vitro. Plectin targeting shows potential as a strategy to inhibit tumor invasiveness as shown in cultured tumor spheroids while oral administration of plecstatin-1 to mice reduces tumor growth more efficiently in the invasive B16 melanoma than in the CT26 colon tumor model.


Inorganic Chemistry | 2017

Introducing the 4-Phenyl-1,2,3-Triazole Moiety as a Versatile Scaffold for the Development of Cytotoxic Ruthenium(II) and Osmium(II) Arene Cyclometalates

Christoph A. Riedl; Lea S. Flocke; Michaela Hejl; Alexander Roller; Matthias H. M. Klose; Michael A. Jakupec; Wolfgang Kandioller; Bernhard K. Keppler

Herein we report the synthesis, anticancer potency in vitro, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) organometallics of the general form [(η6-p-cym)RuCl(κ2-C^N-L)] with varying substituents in postion 1 of the 1,2,3-triazole moiety. These cyclometalates were characterized by standard analytical methods and their structures unambiguously assigned by single crystal X-ray crystallography. The anticancer activity of these novel compounds was tested in the human tumor cell lines A549 (non-small cell lung cancer), SW480 (colon adenocarcinoma), and CH1/PA-1 (ovarian teratocarcinoma), and preliminary structure-activity relationships were derived from the obtained data sets. Various representatives exhibit promising antineoplastic effects with IC50 values down to the low micromolar range. The compounds readily formed stable DMSO adducts after aquation in DMSO-containing solution, but employing DMSO as solubilizer in cytotoxicity assays had no pronounced effect on the cytotoxicity, compared to analogous experiments with DMF for most compounds. We isolated and characterized selected DMSO adducts as triflate salts and found that they show activities in the same range as the parent chlorido metalacycles in MTT assays with the use of DMSO. Osmium(II) cyclometalates exhibited higher antiproliferative activities than their ruthenium(II) counterparts. The IC50 values within each metal series decreased with increasing lipophilicity, which was attributed to higher cellular accumulation. Investigations on their mode of action revealed that the prepared organometallics were unable to inhibit topoisomerase IIα. Still, the most cytotoxic representatives 2b and 3b showed pronounced effects on cell cycle distribution.


Bioconjugate Chemistry | 2017

Multifunctional αvβ6 Integrin-Specific Peptide–Pt(IV) Conjugates for Cancer Cell Targeting

Anne C. Conibear; Sonja Hager; Josef Mayr; Matthias H. M. Klose; Bernhard K. Keppler; Christian R. Kowol; Petra Heffeter; Christian F. W. Becker

Increasing the specificity of cancer therapy, and thereby decreasing damage to normal cells, requires targeting to cancer-cell specific features. The αvβ6 integrin is a receptor involved in cell adhesion and is frequently up-regulated in cancer cells compared to normal cells. We have selected a peptide ligand reported to bind specifically to the β6 integrin and have synthesized a suite of multispecific molecules to explore the potential for targeting of cancer cells. A combination of solid-phase peptide synthesis and chemoselective ligations was used to synthesize multifunctional molecules composed of integrin-targeting peptides, cytotoxic platinum(IV) prodrugs, and fluorescent or affinity probes joined with flexible linkers. The modular synthesis approach facilitates the construction of peptide-drug conjugates with various valencies and properties in a convergent manner. The binding and specificity of the multifunctional peptide conjugates were investigated using a cell line transfected with the β6 integrin and fluorescence microscopy. This versatile and highly controlled approach to synthesizing labeled peptide-drug conjugates has the potential to target potent cytotoxic drugs specifically to cancer cells, reducing the doses required for effective treatment.


Monatshefte Fur Chemie | 2018

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

Matthias H. M. Klose; Anna Schöberl; Petra Heffeter; Walter Berger; Christian G. Hartinger; Gunda Koellensperger; Samuel M. Meier-Menches; Bernhard K. Keppler

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.Graphical abstract


Journal of Biological Inorganic Chemistry | 2017

EGFR-targeting peptide-coupled platinum(IV) complexes

Josef Mayr; Sonja Hager; Bettina Koblmüller; Matthias H. M. Klose; Katharina Holste; Britta Fischer; Karla Pelivan; Walter Berger; Petra Heffeter; Christian R. Kowol; Bernhard K. Keppler

The high mortality rate of lung cancer patients and the frequent occurrence of side effects during cancer therapy demonstrate the need for more selective and targeted drugs. An important and well-established target for lung cancer treatment is the occasionally mutated epidermal growth factor receptor (EGFR). As platinum(II) drugs are still the most important therapeutics against lung cancer, we synthesized in this study the first platinum(IV) complexes coupled to the EGFR-targeting peptide LARLLT (and the shuffled RTALLL as reference). Notably, HPLC–MS measurements revealed two different peaks with the same molecular mass, which turned out to be a transcyclization reaction in the linker between maleimide and the coupled cysteine moiety. With regard to the EGFR specificity, subsequent biological investigations (3-day viability, 14-day clonogenic assays and platinum uptake) on four different cell lines with different verified EGFR expression levels were performed. Unexpectedly, the results showed neither an enhanced activity nor an EGFR expression-dependent uptake of our new compounds. Consequently, fluorophore-coupled peptides were synthesized to re-evaluate the targeting ability of LARLLT itself. However, also with these molecules, flow cytometry measurements showed no correlation of drug uptake with the EGFR expression levels. Taken together, we successfully synthesized the first platinum(IV) complexes coupled to an EGFR-targeting peptide; however, the biological investigations revealed that LARLLT is not an appropriate peptide for enhancing the specific uptake of small-molecule drugs into EGFR-overexpressing cancer cells.


Analyst | 2017

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

Matthias H. M. Klose; Michaela Hejl; Petra Heffeter; Michael A. Jakupec; Samuel M. Meier-Menches; Walter Berger; Bernhard K. Keppler


Metallomics | 2018

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

Matthias H. M. Klose; Sarah Theiner; Christoph Kornauth; Samuel M. Meier-Menches; Petra Heffeter; Walter Berger; Gunda Koellensperger; Bernhard K. Keppler


European Journal of Inorganic Chemistry | 2017

Low generation PAMAM dendrimers as drug carriers for Pt(IV) complexes

Markus Galanski; Nadine S. Sommerfeld; Michaela Hejl; Matthias H. M. Klose; Ekaterina Schreiber-Brynzak; Andrea Bileck; Samuel M. Meier; Christopher Gerner; Michael A. Jakupec; Bernhard K. Keppler


Angewandte Chemie | 2017

Ein Organoruthenium-Tumortherapeutikum mit unerwartet hoher Selektivität für Plectin

Samuel M. Meier; Dominique Kreutz; Lilli Winter; Matthias H. M. Klose; Klaudia Cseh; Tamara Weiss; Andrea Bileck; Beatrix Alte; Johanna C. Mader; Samir Jana; Annesha Chatterjee; Arindam Bhattacharyya; Michaela Hejl; Michael A. Jakupec; Petra Heffeter; Walter Berger; Christian G. Hartinger; Bernhard K. Keppler; Gerhard Wiche; Christopher Gerner


Dalton Transactions | 2018

N- and S-donor leaving groups in triazole-based ruthena(II)cycles: potent anticancer activity, selective activation, and mode of action studies

Christoph A. Riedl; Michaela Hejl; Matthias H. M. Klose; Alexander Roller; Michael A. Jakupec; Wolfgang Kandioller; Bernhard K. Keppler

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Petra Heffeter

Medical University of Vienna

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Walter Berger

Medical University of Vienna

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Beatrix Alte

Medical University of Vienna

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