Cancer is a disease that poses a major global health challenge. Enzymes of the DNA topoisomerase family comprise established targets for the treatment of cancer. Here, we focused on the human DNA topoisomerase IIα (topo IIα), which has a distinct role in DNA replication and is more pronounced in rapidly dividing cells, including cancer cells. Our goal was to inhibit the topo IIα by stopping its catalytic cycle via binding of a small ligand to the ATP target binding site at the N-terminal domain of the enzyme.
Using two substituted 1H-indazoles, with inhibitory activity on topo IIα (starting compounds I and V), we synthesized new analogs to expand their structure-activity relationship (SAR). In the first step, 6 analogs of starting compounds were synthesized. Subsequently, we studied the role of the 1H-indazole scaffold and the location of the proton donor on the heterocycle. Two different 1H-indole carboxylic acids were used in the synthesis of new analogues. We synthesized 9 new compounds 7-15. To extend the SAR of 1H-indazoles, 9 commercially available compounds 16-24 were acquired. All synthesized compounds were evaluated using spectroscopic methods and their physicochemical properties were determined. The biological activity of topo IIα was evaluated for all compounds using HTS relaxation test.
In the group of newly synthesized 1H-indazoles weak topo IIα inhibitory activity was detected for three compounds, the highest for compound 3 (RA (250µM) = 69 %). For commercially available 1H-indazoles, weak activity was also detected for compounds 20 (RA (250µM) = 74 %), 17 and 21. Thus, the introduced changes did not improve the inhibitory activity of 1H-indazoles compared to the starting compounds. In the group of 1H-indoles with carboxylic acid at the substitution site 2, weak activity was detected for two compounds, 9 (RA (250µM) = 71 %) and 8, and in the group of 1H-indoles with carboxylic acid at the substitution site 5 two more compounds 15 (RA (250µM) = 76 %) and 13 were identified. Hence, we discovered four new 1H-indole inhibitors of topo IIα. For two 1H-indazoles 3 and 20, which showed weak inhibitory activity, we also predicted their binding to the targeted ATP binding site using the molecular docking. In addition to synthesizing new compounds, we thus obtained valuable SAR information about substituted 1H-indazoles and 1H-indoles as potential inhibitors of the human DNA topoisomerase IIα, which will serve in further development of this group of compounds as anticancer agents.
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