Die Synthese von Resveratrol-Photoprodukten und Modelluntersuchungen zur Komplexchemie und Bioaktivität von Cuprizon

Fries, Martin; Albrecht, Markus (Thesis advisor); Clarner, Tim (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021

Abstract

The first part of this work deals with the photoinduced cyclization of Trimethoxystilbene to Trimethoxyphenanthrene and the cyclization of resveratrol to Trihydroxyphenanthrene. It has been possible to carry out extensive reaction optimization, which is why it is now possible to produce Trimethoxyphenanthrene almost quantitatively. The production of Trihydroxyphenanthrene was also successful, but purification proved difficult. Performed bioactivity tests of the prepared compounds show that Trimethoxyphenanthrene is not biologically active. In contrast, Trihydroxyphenanthrene shows 90% inhibition. In addition to the photochemical work of resveratrol, a UV/VIS technical investigation of cuprizone and BiMPi in combination with copper salts is also undertaken. In summary, it can be said that the two tested cuprizone-copper complexes, differ significantly in their effect. For example, copper(II)chloride in combination with cuprizone and Oxalyldihydrazide shows a linear increase in absorption with no sign of saturation. For copper(II)acetate, on the other hand, it is observed that the intensity of the absorption with both cuprizone and Oxalyldihydrazide runs into a plateau from the addition of 2 equivalents of copper salt. Furthermore, BiMPi with copper(II)chloride shows the formation of a complex, which, however, decays after a short time. The only exception is the BiMPi:copper(II)chloride ratio of 2:1, and it has been possible to obtain a crystal of this complex. The investigation of an observed Tyndall effect by TEM confirmed the assumption that nanoparticles are present in the solution. However, the images also suggest that damage to the particles occurs due to the drying process. Efforts to find a suitable surfactant that would provide sufficient stabilization of the particles yielded most promising results. With this surfactant PVP 40000 g/mol it is possible to stabilize the particles over a limited period of time at a very good particle size of about 15 nm and a PDI of 0.3. Furthermore, experiments are also being undertaken to make cuprizone analogs accessible for bioactivity testing. A cuprizone derivative, BiMPi, has been successfully synthesized and characterized with excellent water solubility of over 300 mg/mL. The tests performed with it, indicate that it has a congruent response of cells as cuprizone. This makes BiMPi suitable as a potential in vitro replacement for cuprizone. In addition to BiMPi, several other derivatives are being tested for biological activity. A rapid assay reveals that compounds 24b,d, 25b and 27a show inhibition of SOD activity, with no effect on XO, which is also present. These promising compounds should be tested for further biological activity, using the gene expression experiments already performed for BiMPi. In the final part of the work, cyclic cuprizone analogs were successfully prepared. It cannot be excluded that this new structural element is responsible for the biological activity of cuprizone in the numerous medical studies. Which is why the compounds produced are interesting. With a water solubility of 190 mg/mL, the compound 46 prepared has a sufficient water solubility to be used for in-vitro assays. Bioactivity tests such as SOD, LDH, CTB can provide valuable information on whether the cyclic structural element is indeed responsible for the bioactivity of cuprizone.

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