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Pfeiffer H.,University of Würzburg | Dragoun M.,Abteilung fur Padiatrische Onkologie | Prokop A.,Abteilung fur Padiatrische Onkologie | Schatzschneider U.,University of Würzburg
Zeitschrift fur Anorganische und Allgemeine Chemie | Year: 2013

A series of seven molybdenum(II) allyl dicarbonyl complexes of the general formula [Mo(allyl)(CO)2(N-N)(py)]+, in which N-N is a bidentate chelating polypyridyl ligand with variable aromatic surface area, was synthesized by a new two-step approach and fully characterized by IR and NMR spectropscopy, ESI mass spectrometry, and elemental analysis. The n-octanol/water partition coefficient logP increased with the size of the N-N ligand from -0.4 to +1.8. The biological activity on adherent HT-29 and MCF-7 as well as non-adherent NALM-6 human cancer cell lines was studied with various assays, allowing also an insight in the mechanism of cell death. Most of the title compounds showed high antiproliferative activity in the low micromolar concentration range on all three cell lines tested, which however did not correlate much with the logP values determined. Apoptosis could be demonstrated as the major pathway of cell death for selected compounds and cell lines, setting on at 5 μM for the most active complex. Interestingly, no difference in apoptosis induction was observed between MCF(+/-) cell lines differentiated by expression of pro-apoptotic enzyme caspase-3 (+) or a lack thereof (-). This indicates an apoptosis induction pathway, which is independent of caspase-3. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Koster S.D.,Ruhr University Bochum | Alborzinia H.,University of Heidelberg | Can S.,University of Heidelberg | Kitanovic I.,University of Heidelberg | And 7 more authors.
Chemical Science | Year: 2012

Solid-phase peptide synthesis (SPPS) is a versatile technique for the assembly of small to medium size peptides, that can help in the delivery of bound metal complexes to certain cellular compartments, for example in cancer cells. This work shows a new route to gold-peptide bioconjugates via a non-catalyzed [3 + 2] cycloaddition reaction of gold azides with alkynyl peptides. Gold(i) tetrapeptide conjugates with a mitochondria-targeting sequence were synthesized and display prolonged stability in the presence of thiol-containing biological media. Their antiproliferative potency against selected cancer cells (2-50 μM) corresponds to the lipophilicity of the conjugates. The cellular uptake of Au, determined by atomic absorption spectroscopy (AAS), shows that high initial uptake equals strong cytotoxicity. Respiration and acidification rates react immediately upon treatment with the Au-peptide conjugates, and a terminal breakdown of essential cellular functions is complete within ca. 12 h at most, as observed by online monitoring of the cancer cell metabolism in a microfluidic biosensor device (Bionas sensorchip system). The mode of action of these Au-peptide bioconjugates was elucidated by a variety of biochemical and cell biological experiments. First, a strong selective inhibition of the enzyme thioredoxin reductase (TrxR), a regulator of cellular redox processes, was found. In this context, elevated levels of reactive oxygen species (ROS) and strong effects on the respiration of isolated mouse liver mitochondria were found. These finally lead to cell death via apoptotic pathways, as indicated by flow cytometry, low mitochondrial membrane potential (MMP) and DNA fragmentation. Intriguingly, cisplatin-resistance in p53-mutant MDA-MB231 breast cancer cells could be overcome by the Au-peptide conjugates presented herein. © 2012 The Royal Society of Chemistry.

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