Cancer represents one of the greatest global health problems. Among other characteristics, it is marked by an elevated concentration of heat shock proteins (Hsp), which help in the correct folding of client proteins to their native conformation within cells. Protein homeostasis is crucial for cell growth and reproduction, making the inhibition of Hsp activity an intriguing therapeutic approach for cancer treatment. One such Hsp is the protein Hsp90, whose expression is significantly increased in cancer, and whose inhibition greatly impacts the survival ability of cancer cells. One of the possible ways to inhibit Hsp90 includes the inhibition of protein-protein interaction between Hsp90 and its cochaperone Cdc37, which is largely responsible for delivering kinases to Hsp90.
The master's thesis aimed to optimize previously synthesized compounds by researchers at the Department of Pharmaceutical Chemistry, UL FFA, with the desired inhibition of the interaction between the proteins Hsp90 and Cdc37. At the same time, we wanted to evaluate the relationship between the structural properties of our ligands and their antiproliferative effect on the MCF-7 cancer cell line. For this purpose, we synthesized nine new pyrimidine-based compounds. We designed them from the basic N-methyl-N-phenethylbenzamide skeleton, which continued into the pyrimidine skeleton. The basis for the optimization were the previously synthesized compounds TNG-116 and TNG-112, where instead of a CH2-CH2-O linker between the N-methylamide and benzene, we inserted a CH2-CH2 linker. To evaluate the influence of para and meta substitution of the central benzene ring on the activity of the analogs and their fitting into the binding site, we designed two libraries of compounds. In both libraries, we simultaneously introduced various aliphatic heterocycles at position 4 of the pyrimidine ring and investigated the impact of their substitution.
Biological testing on the MCF-7 cells revealed the importance of an additional hydrogen bond acceptor at the CH2-CH2-O linker. We found that the functional groups of the compound at position 4 of the pyrimidine heterocycle are unlikely to form ionic interactions with the binding site, whereas the ability to form additional acceptor hydrogen bonds contributes to binding at the same site. We also concluded that excessively increasing the size of the aliphatic heterocycle and meta substitution on the benzene ring are unfavorable. Among the newly synthesized compounds, N-methyl-N-phenethyl-3-((6-(pyrrolidin-1-yl)pyrimidin-4-yl)amino)benzamide (9e) achieved the lowest mean inhibitory value IC50 of 29 μM, which thus serves as one of the starting points for further optimization.
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