Cancer is the second leading cause of death in Western civilisation. Its incidence is higher every year but due to early detection of the disease and more successful treatment options, its mortality rate is decreasing. Cancer cells face many challenges during their development in the human body. One of the biggest obstacles are misfolded proteins (oncoproteins) that are normally subject to degradation. The formation of cancer cells (carcinogenesis) creates a stressful environment leading to the activation and induction of heat shock proteins, which promote cancer development and growth by stabilizing oncoproteins, allowing them to reach their full potential. Heat shock proteins are fundamentally responsible for proteostasis and client protein folding but during carcinogenesis their mechanism of action is altered and abundantly utilised by cancer cells. Many oncoproteins responsible for cancer development interact with heat shock protein 90 (Hsp90). Hsp90 therefore represents a promising target for the development of new cytotoxic agents.
In this master's thesis, we investigated the influence of halogen atoms on the inhibitory potential of new allosteric piperidine-based inhibitors of the Hsp90 C-terminal domain. The basis of our research was a compound with known inhibitory properties. We retained the structural elements responsible for the interaction with Hsp90 and focused solely on the modification of the aromatic ring on the left side by introducing different halogen atoms. We prepared four new compounds, which we biologicaly evaluated with the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) metabolic assay on MCF-7 human breast cancer cells and determined their IC50 values. This provided insightful information, which helped evaluate the ability of the halogens to form halogen bonds with the target, compare our compounds with other Hsp90 inhibitors and establish a structure-activity relationship.
The test results led to the conclusion that substitution of the aromatic ring in both meta and para positions is critical for inhibition in the low micromolar range. Compound 17 had the lowest IC50 value (IC50 = 5.58 ± 0.75 µM) and is therefore the most potent inhibitor. Compared to compound TZZ-11, which served as the reference compound, both compounds 15 and 17 were found to be more potent, while compounds 19 and 11 were not. This led to the conclusion that chlorine and bromine atoms are the best aromatic substituents. This is due to their atom size, which enables them to form the strongest interactions with the target.
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