Cancer is one of the most prevalent and deadly diseases in a modern world where the age of the population is increasing. Many research groups are focused on developing agents that selectively affect cancer cells while having little effect on healthy cells.
Stress proteins or heat shock proteins of 90 kDa (Hsp90) are an increasingly important target in the development of new anticancer agents. They play an important role in the activation, proper folding and degradation of misfolded proteins. At the same time, they are involved in a number of signalling pathways that lead to the formation of malignant cells. Hsp90 inhibitors are divided into inhibitors acting on the N-terminal domain and the C-terminal domain. A major drawback of N-terminal inhibitors is the induction of a heat shock response, which counteracts the action of Hsp90 inhibitors and reduces their efficacy. Research is increasingly focusing on the development of C-terminal inhibitors that lack the heat shock response.
In the framework of the master's thesis, we evaluated the effect of C-terminal Hsp90 inhibitors synthesised at the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, on cancer cell proliferation. Their activity was studied in PC3 MM2 luc cell lines by luciferase refolding assay and in MCF-7, SK-BR-3 and SK-N-MC cell lines by MTS ((3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) proliferation assay.
Based on the results obtained, we concluded that the activity is favourably influenced by the presence of at least one basic centre and two aromatic rings. The distance between the basic centre and the aromatic ring is of a key importance. We also confirmed that substitution of the aromatic ring by halogens contributes to a stronger effect of the inhibitor. Although further tests should be performed focusing more on the influence of the bound halogen on the aromatic ring, we also observed a stronger activity of compounds where the aromatic ring was substituted with chlorine atom instead of fluorine atom.
With this thesis, we were able to evaluate the activity of C-terminal domain inhibitors that are structurally very different from each other and thus investigate which structural elements are necessary for their antiproliferative activity.
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