Heat shock proteins 90 (Hsp90) are chaperones that promote proper folding of newly synthesized or misfolded proteins, thereby counteracting aggregation. They are involved in important cellular processes and regulatory pathways, such as cell cycle control, cell viability, apoptosis, protein folding and degradation, and signal transduction. The Hsp90 protein consists of 3 major domains, the N-terminal domain, the C-terminal domain, and the middle domain. Hsp90 inhibitors can be classified into two categories: N-terminal domain inhibitors and C-terminal domain inhibitors. The original Hsp90 inhibitors act by binding to the ATP pocket of the N-terminal domain and inhibit the ATPase activity of Hsp90. Hsp90 is an important target for the development of new antitumor agents because cancer cells are more sensitive to Hsp90 inhibitors compared to healthy cells.
In this master's thesis, we synthesized four potential inhibitors of the C-terminal domain of Hsp90 using a triazole as a backbone. The compounds are analogues of the previously prepared compound TJD-163, and they all have in common that they have different substituents at position 4 of the triazole ring containing α-trifluoromethyl benzocycloalkanol. At position 1 of the triazole ring, they are all substituted with a 4-(piperazin-1-ylcarbonyl)phenyl group. The final compounds were synthesized by attaching various alkynes to the starting compound, an aryl azide, using a click reaction. These were prepared by asymmetric reduction of 2-trifluoromethyl ketones to give enantiomerically pure alcohols, which were then O-alkylated with propargyl bromide. A Noyori-Ikariya type ruthenium catalyst was used as the catalyst. The progress of the reactions was monitored by thin layer chromatography (TLC), the purity of the final compounds was checked by high performance liquid chromatography (HPLC), and the structure was determined by nuclear magnetic resonance (NMR) and mass spectrometry MS. Finally, the prepared compounds were tested for their inhibitory activity on the MCF -7 breast cancer cell line and compared with compound TJD-163. Compound 25 had the strongest inhibitory activity (IC50 (MCF-7) = 14.15 ± 4.78 µM). It differs from compound TJD-163 by an additional methoxy group at position 6 of the tetralol fragment. Compound 16, to which indanol is bound instead of tetralol, had the weakest inhibitory effect. These results contribute to the understanding of the relationship between the structure and function of triazole Hsp90 inhibitors.
|
