The number of new cancer cases and cancer mortality have increased in Slovenia in recent years. With the early treatment and proper selection of cancer therapy, patients can be cured or the time to progression of the disease can be prolonged. Therefore, many researchers are looking for new agents that inhibit the abnormal and uncontrolled growth of cancer cells. Inhibitors of heat shock protein 90 are being intensively investigated, because heat shock proteins are more highly expressed in cancer cells than in normal cells and enable them to survive in adverse conditions of the tumor microenvironment. Inhibition of the heat shock protein 90 downregulate several signalling pathways simultaneously by acting on proteins that depend on this chaperone and thus reduces the growth of cancer cells.
In this work, we synthesised and evaluated a series of potential inhibitors of the C-terminal domain of Hsp90. We started from compounds previously prepared at the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, which have shown activity on Hsp90 in in vitro assays in addition to their effect on DNA topoisomerase Iiα. All of our compounds had a N-(2-benzyloxy)phenylpyrrolamide basic structure. All compounds were investigated physicochemically using nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, and high-resolution liquid chromatography. The compounds were also evaluated biologically using the MCF-7 breast cancer cell line.
As a part of the biological testing, compounds 8, 10, 12, 14, 16, 23, and 24 were evaluated on the MCF-7 breast cancer cells using the MTS assay. Activity was expressed as mean inhibitory concentration (IC50). Most of the tested compounds showed potent inhibitory effects on the MCF-7 cell viability with IC50 values in the low micromolar or high nanomolar range. Compound 23 showed the best inhibitory activity with a mean inhibitory concentration of 0.85 μM. This was followed by compounds 24 and 14 with mean inhibitory concentrations of 0.92 μM and 0.94 μM, respectively. The results of biological testing showed that slightly more flexible molecules have a better inhibitory effect because the position of the basic centre in these molecules is more favourable for binding to the C-terminal domain of Hsp90 than in more rigid molecules. Overall, the new N-(2-benzyloxy)phenylpyrolamides prepared in the master’s thesis have shown promising effect on the viability of MCF-7 breast cancer cell line.
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