초록/요약

Topoisomerase II poison blocks the transitorily generated DNA double-strand breaks (DSBs) from religation, thereby causes severe DNA damage and gene toxicity. While topoisomerase II catalytic inhibitor does not form cleavable DNA-enzyme complex because its function attributes to inhibition of the catalytic steps of the enzyme such as before generating DNA DSBs or in the last step of the catalytic cycle after religation. It has been reported that the stabilizing effect of etoposide on transient cleavable DNA-topoisomerase II beta complex attributes to its secondary malignancy. Therefore, topoisomerase II alpha has been considered as more attractive target than topoisomerase II beta for the development of chemotherapeutic agents. In the previous work, we reported compounds I and II as novel topoisomerase II alpha catalytic inhibitors targeting for ATP binding site of human topoisomerase Ha ATP-binding domain. As a continuous work, we have designed and synthesized 43 compounds of C1-O-alkyl and arylalkyl substitiuted compounds with or without methoxy group on ring A. In the topoisomerase II alpha inhibitory test, among the tested C1-O-4-chlorophenethyl substituted compounds 37 and 47 were more active than others, and compound 37 showed strongest topoisomerase II alpha inhibitory activity with 94.4% and 23.0% inhibition, respectively, at 100 and 20 mu M. Compounds 37 and 47 have also showed much enhanced cytotoxic activity against T47D cells; IC50 (Ad): 0.63 +/- 0.01 and 0.19 +/- 0.02, respectively, which are stronger than reference drugs. Band depletion assay and cleavage complex assay results showed compounds 37 and 47 were potential topoisomerase II alpha catalytic inhibitor with low DNA damage. (C) 2016 Elsevier Masson SAS. All rights reserved.