3-(3-Butylamino-2-hydroxy-propoxy)-1-hydroxy-xanthen-9-one acts as a topoisomerase IIα catalytic inhibitor with low DNA damage

• Compound 4 showed strongest topo IIα inhibitory activity at 10 μM.
• Compound 4 showed efficient cytotoxicities against T47D and HCT15 cells.
• Compound 4 induced much less DNA damage than etoposide in HCT15 cell.
• Compound 4 was an ATP-competitive human topo IIα catalytic inhibitor.

As a continuous study we prepared several alkylamine (n = 3–6) and evaluated for the pharmacological activity and mode of action. In the topoisomerase IIα (topo IIα) inhibition test, compound 4 showed strongest inhibitory activity among the compounds at 10 μM. Inhibitory activities of the compounds are in the order of 4 (n = 4) > 1 (n = 3) >> 5 (n = 5) ≈ 6 (n = 6); 8 (n = 4) >> 7 (n = 3) ≈ 9 (n = 5) ≈ 10 (n = 6) where n is the number of carbon in the aliphatic side chain in ring C and compounds 7–10 have additional methoxy group in ring A compared to compounds 1, 4–6. Compound 4 showed efficient cytotoxicities against T47D (IC50: 0.93 ± 0.04 μM) and HCT15 (IC50: 0.78 ± 0.01 μM) cells, which are higher than etoposide. Compound 4 was also an ATP-competitive human topo IIα catalytic inhibitor with partially blocking human topo IIα-catalyzed ATP hydrolysis and intercalating into DNA. Compound 4 induced much less DNA damage than etoposide in HCT15 human colorectal carcinoma cells. Overall, compound 4 can be a potential anticancer agent acting as topo IIα catalytic inhibitor with low DNA damage.

Compound 4 was an ATP-competitive human topo IIα catalytic inhibitor with partially blocking human topo IIα-catalyzed ATP hydrolysis and intercalating into DNA. Figure optionsDownload as PowerPoint slide