Cancer has a major global impact on all human society around the world and is one of the most common causes of death. Only in 2018 18.1 million new cases of this complex disease were reported. Because of this resason there exsits a constant emphasis on exploring new active substances that can be used in the effective treatment of cancer. Topoisomerases are molecular motors that enable topological changes of the DNA molecule and are necessary for cell survival and cell division. An important representative is the human DNA topoisomerase IIα, which is a well-known and validated anticancer target. Inhibitors of human topoisomerase IIα are divided according to the mechanism of action, into established topo II poisons and an emerging group of catalytic inhibitors. Because of the cardiotoxicity issues and possible induction of secondary tumors observed primarily during the clinical use of topo II poisons, there is a growing emphasis on the development of catalytic IIα inhibitors expoiting alternative mechanisms of action.
In this Master's thesis, on the basis of the previously aquired Structure-Activity Relationship data (SAR) of the 3,5-disubstituted 1,2,4-oxadiazoles chemical class on the topo IIα enzyme, four starting compounds A-D were selected to guide the sythesis of a new small series of analogs that could act as catalytic inhibitors of topo IIα targeting the ATP binding site. The reactions commenced with the amidoxyme starting compound, which was then O-acylated. Subsequently, a cyclization was carried out to afford a 1,2,4-oxadiazole ring, and at the end the hydrolysis of the amide bond was performed. All compounds were characterized by spectroscopic methods. Altogether 11 target compounds were synthesized, which were biologically evaluated using the HTS relaxation test.
Of all tested oxadiazoles, 5 compounds showed inhibitory properties, with the IC50 values below 1000 μM. The best results were found for a compound 14, with an IC50 value of 186.3 μM. This confirmed that the sulfone group can favorably contribute to the topo IIα inhibitory activity. For the first time oxadiazole derivatives with a free amine group that showed inhibition activity on topo IIα were also discovered . For compound 14, a binding model was also generated by docking the molecule in the ATP binding site of the topo IIα N-terminal domain and thus intermolecular recognition was studied. A cytotoxicity MTS assay on the human breast cancer cell line MCF-7 was performed for this compound and revealed that this compound inhibits the growth of breast cancer cells with the EC50 54,5 μM, which is in the same order of magnitute as clinically used topo II poison etoposide for which an EC50 of 12.6 µM was determined.
In this work, we obtained valuable new information regarding the 3,5-disubstituted 1,2,4-oxadiazoles as topo IIα inhibitors, which will serve to further develop this group to potentially new anticancer agents.
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