The 90-kDa heat shock proteins (Hsp90) are among the most important molecular chaperones involved in regulation of stability, activation and degradation of many client proteins associated with cell growth, proliferation and survival. They interact with more than 400 client proteins, including oncogenic proteins such as EGFR, HER2, Braf, Cdk4 and others. Hsp90 upergulation can lead to excessive aggregation of client proteins, promotion of cell proliferation and angiogenesis, acceleration of the cell cycle and promotion of cell migration and invasion. Hsp90 is thus an attractive therapeutic target for cancer treatment since its inhibition inactivates client proteins and also induces their degradation.
In this master's thesis, we synthesized ten inhibitors of the C-terminal domain of Hsp90, starting from the compound 23 with known antiproliferative activity. We changed the left part of the structure only, while keeping the piperazine structure with the triazole scaffold unchanged. We evaluated the antiproliferative activity of the final compounds in MCF-7 breast cancer cell line using the MTS assay, which is based on the ability of living cells to convert tetrazolium compound (MTS) into colored product formazan. Based on the test results, we explored the relationship between the compound’s structure and activity.
The results demonstrated that all the synthesized compounds, except for the inactive compound 22, displayed more potent antiproliferative activity than the reference compound 23. Compounds 21 (IC50 = 1.3 ± 0.0 μM) and 20 (IC50 = 3.4 ± 0.3 μM), containing methoxynaphthalene (21) and biphenyl (20) moieties in the left part of the structure, showed the most potent antiproliferative activity. These findings indicate that larger lipophilic aromatic systems on the left side of the structure are crucial for potent activity of Hsp90 inhibitors. Additionally, we observed that compounds with double halogen substitution displayed more potent activity compared to those with single halogen substitution. This suggests that these compounds are capable of forming halogen bonds with the binding site of the Hsp90 C-terminal domain. On the other hand, compounds with an unsaturated cyclic system condensed on benzene ring showed weaker activity, possibly due to poor fitting into the hydrophobic pocket or weak interactions in the binding site. These findings have provided valuable insights into the structure-activity relationship of inhibitors targeting the C-terminal domain of Hsp90.
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