Intracellular Diagnostics: Hunting for the Mode of Action of Redox-Modulating Selenium Compounds in Selected Model Systems

Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-)chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the “redox link” which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks

Oxidative stress and electrochemical decontamination procedures in dialysis

Die Zielsetzung dieser Arbeit war die Erforschung und Entwicklung neuer innovativer, ökonomischer und ökologischer Reinigungsmethoden, auf Basis elektrochemischer Verfahren, für Dialyseapparaturen der Firma Fresenius Medical Care. Die Dialyse spielt eine immer größere Rolle bei der Behandlung von Patienten mit Nierenversagen oder chronischen Nierenschäden. Damit nimmt auch die Bedeutung der Entwicklung und Vermarktung von kostengünstigen Reinigungsmethoden für die verwendeten Dialyseapparaturen einen immer höheren Stellenwert ein. Selbst kleinste Einsparungen können hier zu deutlichen Kostensenkungen führen und diese Behandlungsmethode daher auch für Krankenkassen und Patienten erschwinglicher machen. Die hier vorliegende Arbeit beinhaltet die chemischen und biologischen Grundlagen zur Entwicklung einer Reinigungsmethode auf Basis elektrochemischer Erzeugung von reaktiven Sauerstoffspezies (ROS) und deren Anwendung im biologischen System. Des Weiteren werden chemische "Sauerstofflieferanten" zur Verstärkung der Bildung von ROS vorgestellt und elektrochemisch untersucht. Ein zweiter Abschnitt dieser Arbeit beschäftigt sich mit der Erforschung und Entwicklung von neuen Wirkstoffen gegen Oxidativen Stress (OS) auf Basis chinon- und chalkogenhaltiger Derivate und der elektrochemischen Untersuchung von Redoxkatalysatoren gegen oxidativ gestresste Zellen. Schwefelhaltige Naturstoffderivate auf Grundlage des Allicins wurden auf ihre Verwendung als "grüne" Pestizide oder als potentielle Krebswirkstoffe hin analysiert und charakterisiert.The objective of this thesis was the research and development of an innovative, economicaly and environmentally friendly method for cleaning the dialysis equipment of the Fresenius Medical Care Company. Dialysis plays an increasingly important role in the treatment of patients with renal failure or chronic kidney damage. Therefore, the importance of development and commercialisation of new cost-effective cleaning methods in dialysis will also increase. Even the smallest savings can lead to significant cost reductions and this could therefore make this treatment more affordable for patients and for the health insurance funds. The present work involves the chemical and biological basis for the development of a purification method based on the electrochemical generation of reactive oxygen species (ROS) and their application in the biological system. Also presented and electrochemically investigated are chemical "oxygen suppliers" to strengthen the generation of ROS. A second section of this paper deals with the research and development of new drugs against oxidative stress (OS) (quinone-based derivatives) and the electro-chemical study of redox catalysts against oxidatively stressed cells. Sulfur-containing natural derivatives based on the allicin were investigated for their use as "green" pesticides or as potential cancer drugs

Sulfur, selenium and tellurium pseudopeptides: synthesis and biological evaluation.

A new series of sulfur, selenium and tellurium peptidomimetic compounds was prepared employing the Passerini and Ugi isocyanide based multicomponent reactions (IMCRs). These reactions were clearly superior to conventional methods traditionally used for organoselenium and organotellurium synthesis, such as classical nucleophilic substitution and coupling methods. From the biological point of view, these compounds are of considerable interest because of suspected anticancer and antimicrobial activities. While the sulfur and selenium containing compounds generally did not show either anticancer or antimicrobial activities, their tellurium based counterparts frequently exhibited antimicrobial activity and were also cytotoxic. Some of the compounds synthesized even showed selective activity against certain cancer cells in cell culture. These compounds induced a cell cycle delay in the G0/G1 phase. At closer inspection, the ER and the actin cytoskeleton appeared to be the primary cellular targets of these tellurium compounds, in line with some of our previous studies. As most of these peptidomimetic compounds also comply with Lipinski's Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations

Recent Advances in Redox Active Plant and Microbial ProductsFrom Basic Chemistry to Widespread Applications in Medicine and Agriculture /

XIV, 482 p. 173 illus., 68 illus. in color.onlin

Synthesis of amphiphilic seleninic acid derivatives with considerable activity against cellular membranes and certain pathogenic microbes

International audienceSelenium compounds play a major role in Biology, where they are often associated with pronounced antioxidant activity or toxicity. Whilst most selenium compounds are not necessarily hazardous, their often selective cytotoxicity is interesting from a biochemical and pharmaceutical perspective. We have synthesized a series of amphiphilic molecules which combine a hydrophilic seleninic acid head group - which at the same time serves as thiol-specific warhead - with a hydrophobic tail. These molecules possess a surface activity similar to the one of SDS, yet their biological activity seems to exceed by far the one of a simple surfactant (e.g. SDS) or seleninic acid (e.g. phenyl seleninic acid). Such compounds effectively haemolyse Red Blood Cells and exhibit pronounced activity against Saccharomyces cerevisiae. From a chemical perspective, the seleninic warheads are likely to attack crucial cysteine proteins of the cellular thiolstat