Proteins are structurally the most complex and versatile molecules involved in almost every biological process. They consist of amino acid chains that must fold in a proper conformation for a protein to become functional. Appropriate protein folding is not only important to ensure the right function, but also to prevent the manifestation and progression of many diseases, including cancer. Normal protein homeostasis is ensured by molecular chaperones, which prevent improper connections between amino acids and facilitate protein folding.
Heat shock protein 90 (Hsp90) is a molecular chaperone responsible for the correct folding of hundreds of proteins, including many oncoproteins that have a crucial role in malignant transformation. Because of its role in the pathophysiology of cancer, it is a potential target for new chemotherapeutics – inhibitors of Hsp90 ATPase activity. The first Hsp90 inhibitors blocked ATP binding at the N-terminal domain of the protein. Due to toxicity, poor bioavailability, and induction of heat-shock response, their therapeutic potential has been limited, leading to the development of allosteric inhibitors of Hsp90 C-terminal domain.
In the context of this master's thesis, we studied the influence of tertiary amines structure on antiproliferative activity of piperidine-based Hsp90 C-terminal domain inhibitors. Our starting point for the synthesis of the focused library of final compounds was known allosteric Hsp90 C-terminal domain inhibitor. In this way, we retained properties that were identified as important for forming interactions with the target. By varying the amine portion of the parent molecule, five new compounds were obtained. The substituents attached to the piperidine amine of those compounds differ in many properties, including polarity, size, and ability to form different types of interactions. The antiproliferative activity of the final compounds was evaluated in vitro in MCF-7 breast cancer cell lines using colorimetric MTS cell proliferation test. Based on the results, the relationship between structure and activity of final compounds was examined.
The newly synthesized final compounds were, in majority, found to be less active compared to the parent compound and the previously synthesized compounds. The methyl and benzyl groups proved to be the most optimal substituents on the piperidine amine. These results provide important information for further optimization of this class of Hsp90 inhibitors.
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