Heat shock protein 90 (Hsp90) is an important molecular chaperone involved in the folding and stabilization of more than 400 different client proteins and inhibits heat-induced protein aggregation. It is found in high levels in many types of cancer, where it contributes to cancer cell survival. Its inhibition has proven to be a promising strategy for fighting cancer, as it can cause the degradation of client proteins that cancer needs to survive. To date, scientists have discovered several natural and synthetic inhibitors, the first of which inhibited the N-terminal domain of Hsp90. Despite their potent antitumor effects, they could not be developed into effective drugs due to the induction of heat shock response and associated inefficiency, toxicity and poor solubility. Research has therefore expanded to C-terminal domain inhibitors that do not induce heat shock response, resulting in improved solubility and minimal expression of toxicity.
As part of the thesis, we synthesized four potential inhibitors of the C-terminal domain of Hsp90, which contain a triazole backbone in their structure. The synthesis consisted of four steps, where we first prepared an azide and an alkyne, joined them by a click reaction, and finally removed the Boc protecting group to obtain the product in the form of a salt. Various synthesis procedures were used, such as the formation of an amide bond with the help of coupling reagents or with the prior activation of a carboxylic acid to form an acid chloride, Williamson ether synthesis, click reaction, and deprotection of the Boc protecting group. The intermediates and final products were purified and analysed by chromatographic and spectroscopic methods. We determined the effect of the final products on the proliferation of the MCF-7 breast cancer cell line using the MTS cell assay, which is based on the reduction of MTS to a water-soluble formazan derivative. The results showed that two of the prepared compounds, 7 and 10, had stronger activity than the reference compound TJD-52, while the remaining compounds showed weaker inhibitory activity. Compound 10, which has a 3,4-dichlorophenyl ring attached to the central triazole part of the molecule with an ether bond, was the most potent compound in the series. For further optimisation, it would therefore make sense to take compound 10 as the starting compound, which could lead to an even stronger anticancer effect.
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