Cancer is a complex disease caused by changes in the genes responsible for growth and cell division. An important approach to cancer treatment is chemotherapy. An established target of chemotherapy is human DNA topoisomerase IIα (topo IIα), which catalyzes topological changes in the DNA molecule. Its two groups of inhibitors, the clinically used topoisomerase poisons and the catalytic inhibitors, can stop both cell division and DNA transcription, thereby inhibiting cancer cell growth. The limitations of clinical topoisomerase poisons, especially the development of secondary cancers and cardiotoxicity, led to further research towards safer and more effective agents, especially from the class of catalytic inhibitors.
In this master's thesis, we sought to optimize 3,5-disubstituted 1,2,4-oxadiazoles, a well-known class of topo IIα inhibitors. Based on the comparison of binding models of the bithiazole molecule, which acts as an ATP competitive inhibitor of topo IIα, and synthesized compounds of this chemical class from previous research, we introduced an additional methylene group between the oxadiazole and phenyl rings at position 5 to make this section of the molecule more structurally similar to bithiazole. In some compounds, the second phenyl at oxadiazole position 3 was substituted by an additional methyl group. We succeeded in synthesizing 13 such compounds. Evaluation of the topo IIα inhibitory activity using a relaxation assay showed that the introduction of a methylene group leads to non-active compounds. We checked whether the introduction of a methylene moiety was also unfavorable for analogs containing structurally similar heterocycles to our core oxadiazole.
Four commercial compounds were tested and were also found to be inactive. By performing molecular docking calculations, we hypothesized that the loss of activity for more flexible
oxadiazoles might be the result of a more pronounced unfavorable entropy change that occurs when the ligand from solution binds to the ATP binding site compared to more rigid analogs. Oxadiazole derivatives formed fewer interactions and occupied the ATP binding site less optimally than the more active bithiazole.
Although our optimization strategy did not improve the topo IIα inhibitory activity of 3,5-disubstituted 1,2,4-oxadiazoles, the information obtained is important for further development because it indicates that a major structural change in the chemical is required if we are to achieve a significant improvement in topo IIα inhibitory activity.
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