Cancer is the second leading cause of death worldwide. Although there are many types of cancer treatment available, the lack of drug selectivity and their side effects are becoming an increasing health problem. Pharmaceutical companies are exploring novel molecular targets and developing antitumour drugs acting by novel mechanisms.
Heat shock protein 90 (Hsp90) is one of the most abundant cell proteins. It contains three domains: N-terminal, middle and C-terminal domain. It is an ATP dependent molecular chaperone that plays a pivotal role in proteostasis. Hsp90 is responsible for folding, maturation and activation of many proteins called co-chaperones and clients. Most of them can trigger neoplastic changes. This is the reason why Hsp90 has become a promising target in the development of antitumour drugs as we can block many cancer pathways by inhibiting its activity. Hsp90 N-terminal domain has been a focus of research as an attractive anticancer target, but N-terminal inhibitors have often been found as toxic and displayed unwanted side effects. Discovery of another binding site on the C-terminal domain of Hsp90 enables alternative strategy for anticancer therapy. However, complexity and absence of co-crystal structure of C-terminal domain in complex with ligand make development of new Hsp90 C-terminal inhibitors difficult. In this master’s thesis, we synthesized new potential allosteric Hsp90 C-terminal domain inhibitors based on the piperidine scaffold and studied structure-activity relationship.
In the context of the experimental work of this master’s thesis we synthesized six analogues of the virtual screening hit. We introduced amide bond between central rings and evaluated the influence of chain length between the phenol and the basic amine. We explored the role of hydroxyl group in the central part and studied the effect of different substituents on the phenol moiety on compound activity against cancer cell lines. The final compounds were evaluated in vitro for their cytotoxicity in HepG2 liver cancer and MCF-7 breast cancer cell lines. Five of them showed higher activity (IC50= 14 – 29 µM) as the activity of previously discovered virtual screening hit (IC50= 45 µM), while compound 12 was found to be inactive. The results of structure-activity relationship pave the way to further optimisation of this structural class of Hsp90 C-terminal inhibitors.