1. Development of Potential Therapeutics for Treating Sulphite Oxidase Deficiency
Due to a genetic defect, sulphite oxidase, which is responsible for catalysing the last step in sulphur metabolism, might not work. The results are severe neuronal dysfunctions that lead to general underdevelopment, above all of the brain, which usually means that those affected do not reach the end of their first year of life. The only current therapy for the three forms of this illness is the biotechnological synthesis of a molybdopterin precursor and its intravenous administration. As there is only a very small number of cases, there is no commercial interest in this therapy that has only been developed and is used as part of university research. Using the mouse as a model organism, researchers were able to show that the symptoms of the illness could be fully healed through the injection of an organic precursor of the molybdenum cofactor. However, this does not work for “isolated Sulphite Oxidase Deficiency” (iSOD) The studies performed by our research group have proven that the influence of the molybdopterin ligand is primarily limited to the pyran and the pyrazine rings and the most pressing goal is the synthesis of a corresponding model. After developing a synthetic model of this kind, we plan to test it on its possible therapeutic effect with regard to encephalopathy caused by the sulphite oxidase deficiency. This will be carried out at first in cooperation with a microbiology research group (Leimkühler/Potsdam) and later ideally with a medical facility. By doing so, we hope to develop a better method of treatment than the current laborious biotechnological production of the molybdopterin precursor and a way to combat the type of illness that is currently not treatable. The project is a continuation, refinement and enhancement of earlier research approaches and was funded by a ERC Starting Grant from the European Research council from February 2012 to January 2018.
3. Fluorescence-Based Detection of Transition Metals with Dithiolenes
Dithiolenes are also excellent ligands for thiophile metals such as mercury, lead, arsenic, but also nickel. Combining dithiolenes with fluorophores by using suitable linkers has a great potential in the area concerned with fluorescence-based detection or tracking/observation of the corresponding metals, for example in cell samples. The non-innocence of the dithiolene function should guarantee an excellent signal transduction when bound with metal, as these ligands are predestined to establish a compound between the connected metal and fluorophore. Furthermore, the modification of the dithiolenes with further metal-binding groups should enable a greater metal specificity in the further development of the project. My Group is currently developing and optimising different combinations of dithiolene moiety, linker and fluorophore. First results for identifying metals by using different chemosensors have been successful (registered for patent), or are exceedingly promising.
4. Enantioselective Oxidation of Prochiral Sulphoxides with Vanadium-Dithiolene Catalysts
It has already been proven that vanadium compounds are able to catalyse the enantioselective synthesis of sulphoxides, which are valuable reagents in organic synthesis. To this effect, we are currently developing compounds, in which vanadium is combined with dithiolene ligands and testing them for corresponding activity. Based on the non-innocent character of the dithiolenes, we expect to see significant deviations in the reactivity when compared to the compounds which have previously been reported. The reduction of the oxygen which is to be transferred at the vanadium centre, should be simplified by the dithiolene ligands, which can release electrons and should therefore lead to increased efficiency. Conversion, yield and enantioselectivity will be examined in detail.
5. Pentathiepines with Biological Activity
During our work on the synthesis of models for the molybdenum cofactor, by chance we discovered the molybdenum mediated synthesis of N-heterocyclic pentathiepines. Pentathiepines also occur in nature, where they show a particularly fungicidal and antibacterial effect. It has already been shown on synthetic pentathiepines that they can interact with DNA. Our pentathiepines, which contain nitrogen heterocycles, have a previously unknown complexity and we are testing them in various approaches with regard to their interactions with biological systems. Detailed examinations of structure-activity relationships are also currently taking place or are planned