Cancer is alongside cardiovascular diseases one of the main public-health problems worldwide. It is characterised by uncontrolled cell division and cell proliferation into surrounding tissues, where tumour formation begins.
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone, which has an important role in regulation of folding and stability of more than 200 client proteins. Clients control cell cycle and cell survival, and assist in many signalling pathways. In cancer cells, Hsp90 activity is overexpressed to stabilize these clients, which are often mutated and responsible for neoplastic changes.
Inhibition of Hsp90 represents a new therapeutic target for cancer treatment. First Hsp90 inhibitors targeted N-terminal ATP-binding site of the protein. They displayed limited therapeutic potential in anticancer treatment and caused side effects – toxicity and induction of heat shock response. Discovery that novobiocin, first identified Hsp90 C-terminal inhibitor, does not induce heat shock response started a new era of developing novel anticancer inhibitors targeting Hsp90.
Experimental work of this master’s thesis contains synthesis of thirteen potential Hsp90 C-terminal inhibitors with piperidine scaffold based on the reference Hsp90 inhibitor. We studied the role of hydroxyl group on piperidine scaffold by replacing it with an amide bond. We studied structure-activity relationship by changing different lipophilic substituents on the benzene ring, and importance of the basic centre on the morpholine ring. We tested activity of synthesized analogues with MTS test of cell proliferation in human breast cancer cells MCF-7 and liver cancer HepG2 cell line. For the most active compounds, we determined IC50 values in MCF-7 and HepG2 cell lines. Four compounds showed effect on cell proliferation, but only two analogues displayed better activity than reference compound. Results of this master’s thesis have an important contribution to understanding of the structure-activity relationship, which is a basic for further optimization of analogues with improved anticancer activity and higher Hsp90 binding affinity.