Cancer is a very important public health, social and economic problem, as it is one of the most common causes of death in the world, along with cardiovascular diseases. Thus, it is not surprising that one of the main research areas is the discovery of new active substances with anticancer activity.
Heat shock protein Hsp90 is a 90 kDa molecular chaperone, which consists of three structural domains: the N-terminal domain (NTD), the middle domain and the C-terminal domain (CTD). The Hsp90 has an important role in cellular homeostasis, but it also participates in the correct protein folding to achieve bioactive conformation and thus the activation of hundreds of proteins. Many of these are oncoproteins, which are important for cancer cell-specific properties. Hsp90 helps cancer cells overcome many stressful situations and its expression in cancer cells is up to 10 times higher than in normal cells. The first Hsp90 inhibitors discovered were N-terminal domain inhibitors, the main disadvantage of which was induction of the heat shock response. This was soon followed by the important discovery of the allosteric C-terminal domain inhibitors. Since the latter did not induce the heat shock response, the C-terminal domain of Hsp90 became an important target in the development of anticancer drugs.
In the context of this master’s thesis, we synthesized eleven potential new Hsp90 C-terminal domain inhibitors. We performed modification of the left and right parts of the reference compound, while the central part, acting as a spacer between the aromatic ring on the left and the basic center on the right, was retained. On the extreme left part of the molecule, we studied the influence of the orientation of the amide bond and the influence of the binding of various substituents to different sites on the phenyl ring. Moreover, we examined the influence of the introduction of the piperidine scaffold in the right part of the molecule and the influence of the distance between the basic center on the piperidine ring and the aromatic ring. The final compounds were evaluated with measuring of metabolic activity in MCF-7 breast cancer cells and in U2932, SU-DHL-2, SU-DHL-10, WSU-DLCL2 and VAL lymphoma cells. Compared to the reference compound, all synthesized compounds showed significantly stronger cytotoxic activity in MCF-7 cells, most of them also in U2932, SU-DHL-2 and VAL cells. Moreover, synthesized compounds showed weaker cytotoxic activity in SU-DHL-10 and WSU-DLCL2 cells compared to the reference. Therefore, the results of the master's thesis provide us with important information about the structure-activity relationship and represent the basis for further optimization of Hsp90 C-terminal domain inhibitors.