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

As a continuous study we prepared several alkylamine (n = 3-6) and evaluated for the pharmacological activity and mode of action. In the topoisomerase II alpha (topo II alpha) inhibition test, compound 4 showed strongest inhibitory activity among the compounds at 10 mu M. Inhibitory activities of the compounds are in the order of 4 (n = 4) > 1 (n = 3) >> 5 (n = 5) approximate to 6 (n = 6); 8 (n = 4) >> 7 (n = 3) approximate to 9(n = 5) approximate to 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 mu M) and HCT15 (IC50: 0.78 +/- 0.01 mu M) cells, which are higher than etoposide. Compound 4 was also an ATP-competitive human topo Hoc catalytic inhibitor with partially blocking human topo II alpha-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 II alpha catalytic inhibitor with low DNA damage. (C) 2013 Elsevier Masson SAS. All rights reserved.