Cancer remains one of the leading causes of mortality worldwide, since its treatment is one of the greatest challenges of modern medicine due to the complex biology of cancer cells. In recent decades, heat shock protein 90 (Hsp90) has proven to be an extremely promising target for the development of a new, selective antitumour agents. The Hsp90 molecular chaperone is responsible for the proper maturation and function of more than two hundred different cellular proteins, many of which are also involved in the signalling pathways that lead to cancer. By pharmacologically inhibiting the Hsp90 protein, we can cause the simultaneous degradation of various oncogenes and mutated proteins, thereby simultaneously blocking multiple carcinogenesis signalling pathways, leading to cancer cell death. The first known Hsp90 inhibitors have interacted with the ATP binding site at the N-terminal domain of the protein, but these mostly induce a heat shock response leading to toxicity or ineffectiveness of therapy. Due to the limited therapeutic potential of these inhibitors, the discovery of an allosteric binding site at the C-terminal domain of the protein was crucial. Because the mechanism of action of Hsp90 C-terminal domain inhibitors is not related to the induction of a heat shock response, the C-terminal domain has become a new important target for the development of antitumor agents.
As part of the master's thesis, we successfully synthesized six new potential 3,4-dichlorobenzene-based allosteric Hsp90 C-terminal domain inhibitors, which were prepared by modifying the reference compound. In order to deepen the knowledge about the structure-activity relationship, the role of the hydroxyl group on the piperidine ring in the spacer was studied by introducing an amide bond, which was also introduced between the two central rings. We also replaced the morpholine ring with piperidine and investigated the effect of various substituents on the inhibitory activity of the compounds by modifying the basic center. By varying the chain length between the central phenol and the basic center, we also evaluated the effect of distance on the inhibitory activity of the analogues. Subsequently, all final synthesized compounds were evaluated by the MTS test for their effect on cancer cell proliferation, using the human liver cancer HepG2 and breast cancer MCF-7 cell lines as in vitro models. The collected results of biological testing showed that all six final compounds inhibited cell proliferation, but only compound 13 (IC50(HepG2) = 10.7 μM, IC50(MCF-7) = 8.7 μM) displayed more potent antiproliferative activity compared to the reference compound (IC50(HepG2) = 24.7 μM, IC50(MCF-7) = 44.7 μM). The results of the master's thesis represent an important contribution to the understanding of the structure-activity relationship and contribute to further optimization to inhibitors with improved antiproliferative activity.
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