Cancer is one of the most complex and prevalent diseases of modern times, characterised by uncontrolled cell growth and division, as well as the ability to spread throughout the body. Among the most important therapeutic approaches, chemotherapy plays a key role by employing active substances that inhibit the growth and division of cancer cells. A significant target of anticancer agents is the family of DNA topoisomerase enzymes, which enable topological changes in the DNA molecule. Inhibitors of human DNA topoisomerase IIα are used in chemotherapy because they block the enzyme’s activity and thereby suppress the growth of cancer cells. However, their clinical use is limited by serious side effects, including cardiotoxicity and secondary malignancies, resulting from their mechanism of action. In this master’s thesis, we designed, synthesised, and evaluated 3,5-disubstituted 1,2,4-thiadiazoles as inhibitors of DNA topoisomerase IIα. The design was based on a comparison of 3,5-disubstituted 1,2,4-oxadiazoles and substituted bithiazoles, which are ATP-competitive catalytic inhibitors of the enzyme. The structures of the new compounds incorporated an amine linker and a 1,2,4-thiadiazole ring as a synthetically more accessible alternative to the thiazole ring. Enzymatic relaxation assays revealed that the synthesised 3,5-disubstituted 1,2,4-thiadiazoles did not exhibit inhibitory activity, while only the O-acylated side product 13 showed weak activity. Due to the lack of activity, we next examined whether the inclusion of a thiazole ring could enable enzyme inhibition. A smaller series of commercially available 3,5-disubstituted thiazoles was evaluated, among which compounds 15 and 16 showed inhibitory activity comparable to etoposide, a clinically used topoisomerase IIα inhibitor, and a catalytic mode of inhibition. Molecular docking demonstrated that thiazole compound 15 formed energetically more favourable and more uniform binding conformations in the ATP binding site than the analogous compound 3 containing the 1,2,4-thiadiazole ring. The differences are most likely due to the higher torsional strain in the binding pose of compound 3, resulting from repulsion between the additional nitrogen atom of the thiadiazole ring and the nearby amino acid Asp94. The results of this work illustrate how even small structural modifications in a ligand can lead to significant differences in biological activity. The identified chemical class with a thiazole scaffold represents a promising starting point for further development of catalytic topoisomerase IIα inhibitors into anticancer agents that act without the side effects associated with topoisomerase poisons, thus contributing to more effective and safer chemotherapy.
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